Iontophoretic transdermal insulin delivery from apH-controlling hydrogel device: Development, characterization and mechanistic analysis.

摘要

Iontophoresis is a physical method for permeation enhancement that facilitates transport of charged species under the influence of an applied electrical field. Increasing number of charged biopharmaceuticals such as protein/peptides and oligonucleotides coming from the biotech pipeline have been predominantly formulated into injectables, due to difficulties with biological and physicochemical properties of these biomolecules. Iontophoresis is potentially a convenient, non-invasive, compliance-promoting mode of drug delivery that can be applied to minimize the difficulties encountered in the systemic delivery of these drugs. Moreover, in combination with a programmable electronic device, iontophoresis can bring forth the added ability to modulate drug delivery according to a predetermined schedule or in response to a physiologic feedback signal--capabilities essential for the optimal delivery of many biopharmaceuticals.; Electromobility of the drug molecule greatly affects the efficiency of iontophoretic drug delivery. Hence, it is imperative to maintain the drug reservoir pH at a constant optimal level, in order to reproducibly control the charge state of the drug molecule and its delivery. Iontophoresis however involves electrolysis of water, leading to generation of H{dollar}sp+{dollar} or OH{dollar}sp-{dollar} ions and a continuous shift in drug reservoir pH. pH control becomes indispensable in iontophoresis because many of the biotech-derived drugs can exist in multiple charge states (with different electromobilities) depending on solution pH and also because many of these drugs are unstable in pH extremes. In scarce cases, such as Ag/AgCl electrode-based iontophoresis (where water is not electrolyzed), pH control is not required but the toxicity from the iontophoresis of electrolyzed Ag{dollar}sp+{dollar} becomes a greater concern.; This investigation has focused on development and characterization of a pH-controlling hydrogel-based unit-dose device for facilitating the transdermal delivery of insulin. With this focus, (i) a conductive, medically acceptable hydrogel formulation for use as a unit-dose device in iontophoretic transdermal drug delivery was developed, (ii) a thermogelation process for loading insulin into this hydrogel-based device was developed, (iii) a microenvironmental pH-sensing instrumentation was developed and validated for the continuous monitoring of pH during iontophoresis, (iv) kinetics of pH shift during iontophoresis was characterized, (v) an ion-exchange based pH control system was developed, (vi) feasibility of electroregeneration of the pH control system was established, (vii) the kinetic and mechanistic basis of pH control and electroregeneration of the pH control system was determined, and (viii) the possibility of coenhancing insulin delivery, using ethanol and pH control, was established.